Polymeric treatment compositions

ABSTRACT

Compositions are described comprising a polymer; a non-physiological pH solution; and a visualization agent; wherein the polymer is soluble in the non-physiological pH solution and insoluble at a physiological pH. Methods of forming the solutions and polymers are disclosed as well as methods of therapeutic use.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.16/232,929 filed Dec. 26, 2018, which is a continuation of U.S. patentapplication Ser. No. 15/924,028 filed Mar. 16, 2018, now U.S. Pat. No.10,201,562, which is a continuation of U.S. patent application Ser. No.15/142,395 filed Apr. 29, 2016, now U.S. Pat. No. 9,351,993, which is adivisional of U.S. patent application Ser. No. 13/917,323 filed Jun. 13,2013, now U.S. Pat. No. 9,351,993, which claims the benefit of U.S.provisional patent application No. 61/659,916, filed Jun. 14, 2012, theentire disclosures of which are incorporated herein by reference.

FIELD

The present invention relates generally to vascular treatmentcompositions and methods of using these compositions to treat vascularconditions. The compositions can comprise a polymer(s) that transitionfrom a liquid to a solid upon being subject to a physiological pHgenerally found in a tissue or lumen.

BACKGROUND

Embolization is widely used to treat vascular malformations, such asaneurysms, arteriovenous malformations, fistulas, and tumors. Thesemalformations can be treated with a variety of different products,including metallic coils, polymer-metal hybrid coils, microparticles,glues, and foams. However, there remains a need for products that canminimize the risks associated with embolization.

SUMMARY

Treatment compositions are described which comprise a polymer; asolution, e.g., an aqueous solution, having a non-physiological pH; anda visualization agent; wherein the polymer is soluble in thenon-physiological pH solution and insoluble in a physiological pH. Insome embodiments, the polymer is biocompatible.

Methods of delivering a composition as described herein are alsodescribed comprising injecting through a delivery device to a locationwith a physiological pH a liquid embolic composition comprising apolymer, a solution having a non-physiological pH and a visualizationagent, wherein the polymer precipitates when it reaches thephysiological pH and treats the vascular disorder.

Methods of treating a vascular disorder are also described comprisinginjecting through a delivery device into a vessel with a physiologicalpH environment a liquid embolic composition comprising a polymer, asolution having a non-physiological pH and a visualization agent,wherein the polymer precipitates when it reaches the physiological pHand treats the vascular disorder.

The visualization agent can be a particulate and can have aconcentration of about 5% w/w to about 65% w/w. Depending on the type ofimaging used with the present compositions, the visualization agent canbe iodinated compounds, metal particles, barium sulfate,superparamagnetic iron oxide, gadolinium molecules or a combinationthereof.

The polymer can be a reaction product of two or more different monomersor a reaction product of three different monomers. In other embodiments,the polymer can be a reaction product of one or more different monomers.The polymer can have a concentration between about 1% w/w and about 35%w/w. Again, in some embodiments, the polymer can be biocompatible.

The solution having a non-physiological pH can be aqueous and can have apH of less than about 7. In other embodiments, the solution has a pH ofgreater than about 8.

In one embodiment, a composition is described for treating vasculardefects comprised of a biocompatible polymer at a concentration of fromabout 1% to 35% w/w soluble in a solution having a non-physiological pHand insoluble in a physiological pH aqueous solution; a solution havinga non-physiological pH; and a particulate visualization agent at aconcentration of from about 20% w/w to about 60% w/w.

In another embodiment, methods of treating a vascular disorder aredescribed comprising providing a liquid embolic composition comprising apolymer, a solution having a non-physiological pH and a visualizationagent, wherein the polymer is soluble in the solution having anon-physiological pH and insoluble in a physiological pH environment;inserting a delivery device into a vessel or tissue; guiding thedelivery device to an area in need of treatment wherein the area has aphysiological pH; injecting the liquid embolic polymer compositionthrough the delivery device into the vessel at the area in need oftreatment thereby immediately precipitating the polymer and forming asolid polymeric mass; and treating the vascular condition.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates a one month follow-up angiogram of a kidney treatedwith a polymer administered according to Example 5.

FIG. 2 illustrates an x-ray image of an excised kidney treated accordingto Example 5.

FIG. 3 illustrates a histological section of a renal artery filled withliquid embolic polymer.

FIGS. 4A and 4B illustrate pre- and post-treatment angiograms of a retein a pig according to Example 6.

FIGS. 5A and 5B illustrate a post treatment angiogram and apost-treatment CT angiogram of renal vasculature in a rabbit accordingto Example 7 for visualization comparison.

FIG. 6 illustrates a post treatment angiogram using barium sulfate ofrenal vasculature in a rabbit according to Example 8.

FIGS. 7A and 7B illustrate a post treatment angiogram and apost-treatment MR angiogram using tantalum of a renal vasculature in arabbit according to Example 8 for visualization comparison.

DETAILED DESCRIPTION

Described herein generally are vascular treatment compositionscomprising (i) a polymer that can be soluble in solutions atnon-physiological pH and insoluble at a physiological pH or whensubjected to a physiological pH, (ii) an aqueous solution with anon-physiological pH, and (iii) an opacification agent(s) that canpermit visualization in vivo. These compositions can be introducedthrough a delivery device in the liquid state and transition to thesolid state once in the body at subjected to a physiological pH. In oneembodiment, the aqueous solution does not include an organic solvent.

When the polymer is soluble, it can be deployed through a deliverydevice. A delivery device can be any device suitable to deliver theliquid embolic polymers described herein. For example, a delivery devicecan be a catheter or a microcatheter that is deployed to a delivery siteand/or treatment site. However, once precipitated out of solution, thepolymer can be much more difficult to deploy. For example, onceprecipitated, the polymer can in some instances reduce the ability todeliver the polymer through a delivery device. As such, the compositionsand methods described herein can provide a polymer treatment solutionthe can be deployed to a treatment site and having it precipitate onceat the location of interest; the precipitated product would generallynot be deliverable.

Treatment site and/or delivery site as used herein can be any sitewithin a living creature. In some embodiments, the creature is a mammalsuch as a human. Human sites can include blood vessels, renal lumens,fatty tissue, muscle, connective tissue, cerebral spinal fluid, braintissue, repertory tissue, nerve tissue, subcutaneous tissue, intra atriatissue, gastrointestinal tissue, and the like. As a skilled artisanunderstands, the physiological pH of different tissues and lumens withina mammalian body such as a human can vary. A polymeric solution can becustomized for a particular delivery site pH. For example, if thepolymer solution is to be delivered to the stomach, where pHs tend to beacidic, the polymeric solution can be formed in as an alkaline solution.

A function of the polymer, e.g. liquid embolic polymer, can be toprecipitate when coming in contact with blood or other physiologicalfluid at a physiological pH at the intended site of treatment. In someembodiments, physiological pH of the blood stream can be a pH of about7.0, about 7.1, about 7.2, about 7.3, about 7.4, about 7.5, about 7.6,about 7.7 or about 7.8. In another embodiment, physiological pH of thestomach can be a pH of about 3.5, about 3.6, about 3.7, about 3.8, about3.9, about 4.0, about 4.1, about 4.2, about 4.3, about 4.4, or about4.5. In still another embodiment, physiological pH of the intestines candepend on the location within the intestines, but generally can be a pHof about 5.5, about 5.6, about 5.7, about 5.8, about 5.9, about 6.0,about 6.1, about 6.2, about 6.3, about 6.4, about 6.5, about 6.6, about6.7, about 6.8, about 6.9, or about 7.0. Ranges of pH for any of thelists above can be created between any set of values listed.Precipitation of the polymer at a physiological pH can be used toocclude a biological structure and/or a tissue. Control of the liquidembolic polymer's solubility can be achieved by selection of thecomposition of the polymer.

The vascular treatment compositions can comprise a solution at anon-physiological pH. The solution may be aqueous. The solution caninclude a polymer soluble in the solution at non-physiological pH butinsoluble in a physiological pH. Further included in the solution can bea visualization agent. This change in solubility can be a result in achanging viscosity of the polymer within the solution. In otherembodiments, this change in solubility can result in a change in densityof the polymer in solution.

The polymer can be prepared with monomers having ionizable moieties. Insome embodiments, the polymers can be a reaction product of twodifferent monomers, three different monomers, four different monomers,five different monomers or more. A hydrophobic polymer can beconstructed with a minimum amount of ionizable moieties to render thepolymer soluble in non-physiological pH solutions. The ratio of monomerswith ionizable moieties and other monomers can be dependent on thestructure of the monomers and can be determined experimentally.

Amine-containing liquid embolic polymers can be dissolved in a low pHsolution, the amines may be substantially protonated and can enhance thesolubility of the polymer. The resulting solution can be placed inconditions with a physiological pH and the amines can deprotonate andrender the polymer insoluble. Conversely, carboxylic acid-containingpolymers can be dissolved in a high pH solution, the carboxylic acidscan be substantially deprotonated and enhance the solubility of thepolymer. The resulting solution can be placed in conditions with aphysiological pH and the carboxylic acids can protonate and render thepolymer insoluble.

Monomers with ionizable moieties can contain a polymerizable moiety andcan contain an ionizable moiety. Polymerizable moieties can be thosethat permit free radical polymerization, including but not limited toacrylates, methacrylates, acrylamides, methacrylamides, vinyl groups,combinations thereof and derivatives thereof. Alternatively, otherreactive chemistries can be employed to polymerize the polymer, such asbut not limited to nucleophile/N-hydroxysuccinimide esters,nucleophile/halide, vinyl sulfone/acrylate or maleimide/acrylate. Apolymerizable moiety can be an acrylate and/or an acrylamide.

Ionizing moieties can be added to impart the pH-sensitive solubility tothe polymer. Ionizable moieties can include carboxylic acids, amines,and derivatives thereof. Alternatively or additionally, amines protectedusing any suitable technique, such as t-Boc, may be used in thesynthesis of the liquid embolic polymer. Molecules containingpolymerizable and ionizable moieties can include acrylic acid,methacrylic acid, aminopropyl methacrylamide, aminoethyl methacrylamide,N-(3-methylpyridine)acrylamide, N-(2-(4-aminophenyl)ethyl)acrylamide,N-(4-aminobenzyl)acrylamide, N-(2-(4-imidazolyl)ethyl)acrylamide,deverivatives thereof and combinations thereof.

Other monomers can contain a polymerizable moiety and have a structurethat facilitates the desired performance in dissolution or inprecipitation. Polymerizable moieties can be those that permit freeradical polymerization, including acrylates, methacrylates, acrylamides,methacrylamides, vinyl groups, and derivatives thereof. Alternatively oradditionally, other reactive chemistries can be employed to polymerizethe polymer, such as but not limited to nucleophile/N-hydroxysuccinimdeesters, nucleophile/halide, vinyl sulfone/acrylate ormaleimide/acrylate. In one embodiment, polymerizable moieties may beacrylates and acrylamides. In general, any monomer(s) can be utilized toform the described liquid embolic polymers.

Less hydrophobic monomers can require less ionizable monomer to becopolymerized with it to have the desired solubility characteristics.Likewise, more hydrophobic monomers can require more ionizable monomerto be copolymerized with it to have the desired solubilitycharacteristics. Monomers containing moieties available for hydrogenbonding, such as hydroxyl groups, can increase the cohesiveness of theprecipitated polymer. Monomers used can include acrylates andacrylamides such as alkyl acrylates, alkyl alkacrylates, alkylalkacrylamides, and alkyl acrylamides. Acrylates and acrylamides caninclude but are not limited to t-butyl acrylate, t-butyl acrylamide,n-octyl methacrylate, methyl methacrylate, hydroxyethyl methacrylate,hydroxyethyl acrylate, hydroxypropyl methacrylate, hydroxybutylmethacrylate, derivatives thereof and combinations thereof.

In one embodiment, liquid embolic polymers can be polymerized fromsolutions, mixtures, prepolymer solutions of monomers with ionizablemoieties and other monomers. The solvent used to dissolve the monomerscan be any solvent that dissolves or substantially dissolves the chosenmonomers. Solvents can include methanol, acetonitrile, dimethylformamide, and dimethyl sulfoxide.

Polymerization initiators can be used to start the polymerization of themonomers in the solution. The polymerization can be initiated byreduction-oxidation, radiation, heat, or any other method known in theart. Radiation cross-linking of the monomer solution can be achievedwith ultraviolet light or visible light with suitable initiators orionizing radiation (e.g. electron beam or gamma ray) without initiators.Polymerization can be achieved by application of heat, either byconventionally heating the solution using a heat source such as aheating well, or by application of infrared light to the monomersolution.

In one embodiment, the polymerization initiator canazobisisobutyronitrile (AIBN) or a water soluble AIBN derivative(2,2′-azobis(2-methylpropionamidine) dihydrochloride). Other initiatorscan include N,N,N′,N′-tetramethylethylenediamine, ammonium persulfate,benzoyl peroxides, azobisisobutyronitriles and combinations thereof.Initiator concentrations can range from about 0.25% w/w to about 2% w/w,about 0.5% w/w to about 1% w/w, about 0.25% w/w, about 0.5% w/w, about0.75% w/w, about 1% w/w, about 1.25% w/w, about 1.50% w/w, about 1.75%w/w, about 2% w/w, of the mass of the monomers in solution or any rangeor value within the listed percentages. The polymerization reaction canbe performed at elevated temperatures, of about 30° C. to about 200° C.,about 50° C. to about 100° C., about 50° C., about 60° C., about 70° C.,about 80° C., about 90° C. or about 100° C. After the polymerization iscompleted, the polymer can be recovered by precipitation in anon-solvent and dried under vacuum.

The aqueous solution with non-physiological pH can dissolve the liquidembolic polymer. In one embodiment, the aqueous solution does notinclude an organic solvent. Concentrations of the polymer in the aqueoussolution can range from about 2.5% to about 25%, about 5% to about 15%,about 2.5%, about 5%, about 7.5%, about 10%, about 12.5%, about 15%,about 17.5%, about 20%, about 22.5%, about 25% or any percentage orrange of percentages bound by the above percentages. The aqueoussolution can contain the minimum amount of buffer to maintain thenon-physiologic pH after dissolution of the liquid embolic polymer, butnot adversely affect the pH of the patient after administration. Bufferconcentrations range from about 1 mM to about 200 mM, about 10 mM toabout 100 mM, about 20 mM to about 80 mM, about 30 mM to about 70 mM,about 40 mM to about 60 mM, about 45 mM to about 55 mM, about 10 mM,about 20 mM, about 30 mM, about 40 mM, about 50 mM, about 60 mM, about70 mM, about 80 mM, about 90 mM, about 100 mM or any concentration orrange of concentrations within the values listed. In other embodiments,the buffer concentration can be less than about 1 mM or even not used.In one embodiment, the buffer concentration can be about 25 mM.

For liquid embolic polymers containing amines, buffers can includecitrate and acetate and solution pH's can be from about 3 to about 6,from about 3 to about 5, about 3, about 4, about 5 or about 6. Forliquid embolic polymers containing carboxylic acids, buffers can includecarbonate, N-cyclohexyl-2-aminoethanesulfonic acid (CHES),N-cyclohexyl-2-hydroxyl-3-aminopropanesulfonic acid (CAMPSO),N-cyclohexyl-3-aminopropanesulfonic acid (CAPS),3-[4-(2-Hydroxyethyl)-1-piperazinyl]propanesulfonic acid (HEPPS orEPPS), 3-(N-morpholino)propanesulfonic acid (MOPS),4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES),2-(N-morpholino)ethanesulfonic acid (MES) and2-amino-2-methyl-1-propanol (AMP) and solution pH's can be from about 8to about 11, from about 8 to about 10, about 8, about 9, about 10 orabout 11.

Particulate visualization and/or opacification agent or agents canimpart visibility to the liquid embolic polymer when imaged using amedically relevant imaging technique such as fluoroscopy, computedtomography, or magnetic resonance techniques. Visualization of thepolymer under fluoroscopy can be imparted by the incorporation of solidparticles of radiopaque materials such as barium, bismuth, tantalum,platinum, gold, and other dense metals suspended in thenon-physiological pH solution of the liquid embolic polymer. In oneembodiment, the visualization agent for fluoroscopy can be bariumsulfate. Visualization of the polymer under computed tomography imagingcan be imparted by incorporation of solid particles of barium orbismuth. In one embodiment, the visualization agent for computedtomography imaging can be barium sulfate. Concentrations of bariumsulfate to render the liquid embolic visible using fluoroscopic andcomputed tomography imaging can be from about 10% to about 30%, about20% to about 30%, about 30% to about 50% w/w, about 40% to about 45%w/w, about 10%, about 13%, about 15%, about 17%, about 20%, about 23%,about 25%, about 27%, about 30%, about 33%, about 35%, about 37%, about40%, about 43%, about 45%, about 47% about 50% of the non-physiologicalpH solution or any concentration or range of concentrations within thevalues listed.

In another embodiment, the visualization agent for fluoroscopy can betantalum. Concentrations of tantalum to render the liquid embolicvisible using fluoroscopic and/or computed tomography imaging can befrom about 10% to about 30%, about 20% to about 30%, about 30% to about50% w/w, about 40% to about 45% w/w, about 10%, about 13%, about 15%,about 17%, about 20%, about 23%, about 25%, about 27%, about 30%, about33%, about 35%, about 37%, about 40%, about 43%, about 45%, about 47%about 50% of the non-physiological pH solution or any concentration orrange of concentrations within the values listed.

Visualization of the liquid embolic polymer under magnetic resonanceimaging can be imparted by the incorporation of solid particles ofsuperparamagnetic iron oxide or gadolinium molecules polymerized intothe polymer structure or encased into the polymeric structure onceprecipitated. One example visualization agent for magnetic resonance canbe superparamagnetic iron oxide with a particle size of 10 microns.Concentrations of superparamagnetic iron oxide particles to render thehydrogel visible using magnetic resonance imaging range from about 0.01%w/w to about 1% w/w, about 0.05% w/w to about 0.5% w/w, or about 0.1%w/w to about 0.6% w/w of the polymerization solution.

Further, an iodinated compound can be used to impart visibility of theliquid embolic polymer when imaged using fluoroscopy or computertomography. Dissolution of iohexol, iothalamate, diatrizoate,metrizoate, ioxaglate, iopamidol, ioxilan, iopromide, or iodixanol inthe aqueous solution with non-physiological pH can render theradiopaque. Suspension of ethiodol, iodophenylundecylic acid, or both inthe aqueous solution with non-physiological pH can render the liquidembolic polymer radiopaque.

In other embodiments, lipiodol ultra fluid which can include ethylesters of iodized fatty acids of poppy seed oil qs ad for one ampoulewith an iodine content of about 48% (i.e. 480 mg per mL). Additionally,in some embodiments, the use of iodinated compounds can providetemporary radiopacity of the polymer because the iodinated compounds candiffuse or otherwise be carried away from the embolization site by invivo processes.

Polymer visualization under magnetic resonance imaging can be impartedby the incorporation of solid particles of superparamagnetic iron oxideor water soluble gadolinium compounds. In one embodiment, thevisualization agent for magnetic resonance can be superparamagnetic ironoxide with a particle size of about 5 μm, about 10 μm or about 15 μm.Concentrations of superparamagnetic iron oxide particles with any of theabove particle sizes to render the liquid embolic visible using magneticresonance imaging can be from about 0.1% w/w to about 1% w/w, about 0.1%w/w, about 0.2% w/w, about 0.3% w/w, about 0.4% w/w, about 0.5% w/w,about 0.6% w/w, about 0.7% w/w, about 0.8% w/w, about 0.9% w/w, about 1%w/w of the non-physiological pH solution or any concentration or rangeof concentrations within the values listed.

If a particulate visualization agent is utilized, it can be prepared bydissolving the liquid embolic polymer in the aqueous solution withnon-physiologic pH and adding the particulate agent. If a solublevisualization agent is utilized, it can be prepared by dissolving theliquid embolic polymer and water soluble visualization agent in anaqueous solution with non-physiologic pH.

The liquid embolic polymers, solutions and mixtures described herein canbe sterilized without substantially degrading the polymer. Aftersterilization, at least about 50%, about 60%, about 70%, about 80%,about 90%, about 95% about 99% or about 100% of the polymer can remainintact. In one embodiment, the sterilization method can be autoclavingand can be utilized before administration of the polymer.

The liquid embolic polymer formulation can be removed from the vialusing a needle and syringe, the syringe to be later connected to adelivery catheter. To prevent premature liquid embolic polymerdeposition, the delivery catheter can be primed with a bolus of the sameaqueous solution with non-physiologic pH as was used to dissolve theliquid embolic polymer. This flushing can prevent clogging of thedelivery catheter with the liquid embolic polymer. The syringecontaining the liquid embolic formulation can then be connected to theproximal end of a delivery catheter, such as a microcatheter, cannula,or the like, and positioned in the desired vascular or other anatomicsite.

As the liquid embolic formulation is injected, it can push the aqueoussolution with non-physiologic pH flushing solution out of themicrocatheter. The rate of injection can provide differing precipitationamounts and/or precipitation performance. For example, a slowerinjection rate can achieve a more distal penetration of the liquidembolic polymer and a faster injection rate can achieve a more proximalpenetration. In other embodiments, the opposite can be true. In yetanother embodiment, a slower injection rate can result in moreprecipitation whereas a faster injection rate can result in lessprecipitation. In other embodiments, the opposite effect may occur. Thespeed of precipitation can be fast and in some cases can be immediate,e.g. faster than the human eye can discern. In other embodiments, thepolymer can precipitate in less than about 60 s, about 50 s, about 40 s,about 30 s, about 20 s, about 10 s, about 5 s, about 4 s, about 3 s,about 2 s, about 1 s, about 0.75 s, about 0.5 s, about 0.25 s, about 0.1s, about 0.05 s, about 0.01 s, about 0.001 s or any range encompassed byany of these values. For example, in one embodiment, the polymer canprecipitate in between about 0.01 s and about 30 s.

The pH of the aqueous solution can then rapidly change to physiologicalpH as a result of the large buffering capacity of the body's tissues andfluids. Also, a low buffer strength of the solution can lead to therapid change of pH. The progress of the liquid embolic formulationinside the delivery catheter can be observed using an imaging techniquecompatible with the particulate agent or agents selected. With continuedinjection, the liquid embolic formulation can enter a target deliverysite or treatment site.

The large buffering capacity of the body's tissues can cause the fluidsto rapidly deprotonate or protonate the ionizable moieties present onthe liquid embolic polymer, thus reducing the solubility of the liquidembolic polymer and causing it to precipitate from solution. Theprecipitated liquid embolic polymer can entrap the particulate agentsand can provide occlusion of the target site.

The precipitated liquid embolic polymer can be a solid mass ofprecipitate. In some embodiments, the mass can have less than about 20%,about 10%, about 5%, about 1%, about 0.1%, about 0.01, or about 0.001%fragmentation. In some embodiments, the precipitated polymer can becohesive and remain substantially a solid mass.

The precipitated liquid embolic polymer can remain substantially stableonce implanted. For example, the liquid embolic polymer can remaingreater than about 60%, about 70% about 80%, about 90%, about 95%, about99% or about 100% intact after about 5 days, about 2 weeks, about 1month, about 2 months, about 6 months, about 9 months, about a year,about 2 years, about 5 years, about 10 years or about 20 years.

In some embodiments, however, it may be desirable for the precipitatedliquid embolic polymer to degrade over time. In such embodiments, theliquid embolic polymer can degrade to less than about 40%, about 30%about 20%, about 10%, about 5% or about 1% intact after about 5 days,about 2 weeks, about 1 month, about 2 months, about 6 months, about 9months, about a year, about 2 years, about 5 years, or about 10 years.

Further, the liquid embolic polymers once precipitated can be cohesiveenough to stick to the tissue and/or remain in place through frictionwith the tissues. In other embodiments, the precipitated polymer can actas a plug in a vessel held in place by the flow and pressure of theblood itself.

Example 1 Polymer Preparation

To 3 mL of methanol, 1.6 g t-butyl acrylate, 0.4 g of aminoethylmethacrylate, and 10 mg of azobisisobutyronitrile were added. Uponcomplete dissolution, the solution was placed at 80° C. for 8 hr. Then,after cooling to room temperature, the polymer was recovered byprecipitation in ethyl ether and dried under vacuum.

Example 2 Aqueous Solution Preparation

To 1 L of distilled water, 9 g sodium chloride and 6.81 g potassiumphosphate monobasic were added. Upon complete dissolution, the pH of thesolution was adjusted to 3 using phosphoric acid.

Example 3 Preparation of Liquid Embolic Polymer Formulation

To 9 g of the liquid of Example 2, 1 g of the polymer of Example 1 wasadded. Dissolution of the polymer was aided by incubating at 55° C. for24 hr. After complete dissolution, 3 g of barium sulfate was added. Theliquid embolic polymer formulation was then aliquoted into vials andcapped. The vials were autoclaved at 121° C. for 15 min.

Example 4 Effect of Monomer Concentration on Solubility

Using the techniques described in Examples 1 and 2, the polymersdescribed in Table 1 were prepared. The solubility of the polymers wasinvestigated in aqueous solutions at pH 3 (non-physiological) and at pH7.4 (physiological).

TABLE 1 Fraction Fraction t-butyl aminopropyl Soluble Soluble Polymeracrylate methacrylate at pH 3? at pH 7.4? 1 0.88 0.12 No No 2 0.75 0.25Yes No 3 0.73 0.27 Yes No 4 0.68 0.32 Yes Slightly 5 0.65 0.35 YesSlightly 6 0.63 0.37 Yes Yes

The results of Table 1 show how the solubility of the liquid embolicpolymer can be controlled by the amount of ionizable moieties present inthe polymer.

Example 5 In Vivo Evaluation of the Liquid Embolic Polymer in a RabbitKidney

The liquid embolic polymer formulation prepared according to thetechniques of Examples 1, 2, and 3 was utilized for the embolization offive rabbit kidneys. Angiographic occlusion was obtained in all fivekidneys. The kidneys remained occluded angiographically at the follow-upevaluation at 1 month (n=2, FIG. 1) and 3 months (n=3). Histologicalevaluation of the kidneys demonstrated good penetration of the liquidembolic polymer into the vasculature and substantial tissue destructionfrom the removal of the blood supply by the liquid embolic polymer(FIGS. 2 and 3).

Example 6 In Vivo Evaluation of the Liquid Embolic Polymer in a PorcineRete

The liquid embolic polymer formulation prepared according to thetechniques of Examples 1, 2, and 3 was utilized for the embolization ofa rete in an acute pig. At the end of the procedure, angiographicocclusion of the rete was obtained and can be seen when comparing thepre-treatment angiogram in FIG. 4A and the post-treatment angiogram inFIG. 4B.

Example 7 CT Evaluation of the Liquid Embolic Polymer

The liquid embolic polymer formulation prepared according to thetechniques of Examples 1, 2, and 3 was utilized for the embolization ofthe renal vasculature of rabbits. The liquid embolic formulation wasopacified with barium sulfate. At the end of the procedure, the rabbitwas imaged using a CT scanner and differences can be seen when comparingthe pre-treatment angiogram in FIG. 5A and the post-treatment CTangiogram in FIG. 5B.

Example 8 MR Evaluation of the Liquid Embolic Polymer

The liquid embolic polymer formulation prepared according to thetechniques of Examples 1, 2, and 3 was utilized for the embolization ofthe renal vasculature of rabbits. The liquid embolic formulation wasopacified with either tantalum or barium sulfate. At the end of theprocedure, the rabbits were imaged using a MR scanner and differencescan be seen when comparing the pre-treatment angiogram in FIGS. 6 and 7Aand the post-treatment MR angiogram in FIG. 7B.

Example 9 Preparation of Polymer with Increased Cohesivity

To 3 mL of methanol, 0.5 g t-butyl acrylate, 1.2 g hydroethylmethacrylate, 0.3 g of aminoethyl methacrylate, and 10 mg ofazobisisobutyronitrile were added. Upon dissolution of all components,the solution was placed at 80° C. for 8 hr. After cooling to roomtemperature, the polymer was recovered by precipitation in ethyl etherand dried under vacuum.

Example 10 Preparation of Aqueous Solution with Non-Physiological pH andSoluble Iodine

To 1 L of distilled water, 9 g sodium chloride, 6.81 g potassiumphosphate monobasic, and 200 g iohexol were added. Upon dissolution ofall components, the pH of the solution was adjusted to 3 usingphosphoric acid.

Example 11 Preparation of Liquid Embolic Polymer Formulation

To 9 g of the liquid of Example 11, 1 g of the polymer of Example 10 wasadded. Dissolution of the polymer was aided by incubating at 55° C. forseveral hours. After dissolution of the liquid embolic polymer, theliquid embolic polymer formulation was then aliquoted into vials andcapped. The vials were autoclaved at 121° C. for 15 min.

Example 12 Comparison of Liquid Embolic Polymer FormulationPrecipitation

The liquid embolic polymer formulations of Examples 3 and 11 wereevaluated by adding each formulation drop wise into excess phosphatebuffered saline at pH 7.4. The speed of precipitation and cohesivenessof the precipitate were evaluated. Results are included in Table 2.

TABLE 2 Speed of Cohesiveness of Precipitation Precipitate Example 3Formulation Immediate Multitude of polymer pieces Example 11 FormulationImmediate Single piece of polymer

Example 13 Liquid Embolic for Use in a Basic pH Environment

To 3 mL of methanol, 1.6 g t-butyl acrylate, 0.4 g of aminoethylmethacrylate, and 10 mg of azobisisobutyronitrile were added. Upondissolution of components, the solution was placed at 80° C. for 8 hr.After cooling to room temperature, the polymer was recovered byprecipitation in ethyl ether and dried under vacuum. To 1 L of distilledwater, 9 g sodium chloride and 6.81 g potassium phosphate monobasic wereadded. Upon dissolution of components, the pH of the solution wasadjusted to 3 using phosphoric acid.

To 9 g of the liquid, one gram of the polymer was added. Dissolution ofthe polymer was aided by incubating at 55° C. for 24 hr. Afterdissolution of the liquid embolic polymer, 7 g of barium sulfate wasadded to the solution. The liquid embolic formulation was then aliquotedinto vials and capped. The vials were autoclaved at 121° C. for 30 min.

Such a liquid embolic formulation can be implanted as described hereininto intestines or other high pH environments where the polymerprecipitates.

Example 14 Liquid Embolic for Use in an Acidic pH Environment

To 3 mL of methanol, 0.5 g n-octyl methacrylate, 1.5 g of methacrylicacid, and 10 mg of azobisisobutyronitrile were added. Upon dissolutionof components, the solution was placed at 80° C. for 8 hr. After coolingto room temperature, the polymer was recovered by precipitation in ethylether and dried under vacuum. To 1 L of distilled water, 9 g sodiumchloride and 4.2 g sodium bicarbonate were added. Upon dissolution ofcomponents, the pH of the solution was adjusted to 10 using sodiumhydroxide.

To 9 g of the liquid, one gram of the polymer was added. Dissolution ofthe polymer was aided by incubating at 55° C. for 24 hr. Afterdissolution of the liquid embolic polymer, 7 g of barium sulfate wasadded to the solution. The liquid embolic formulation was then aliquotedinto vials and capped. The vials were autoclaved at 121° C. for 30 min.

Such a liquid embolic formulation can be implanted as described hereininto a stomach or other low pH environments where the polymerprecipitates.

Unless otherwise indicated, all numbers expressing quantities ofingredients, properties such as molecular weight, reaction conditions,and so forth used in the specification and claims are to be understoodas being modified in all instances by the term “about.” Accordingly,unless indicated to the contrary, the numerical parameters set forth inthe specification and attached claims are approximations that may varydepending upon the desired properties sought to be obtained by thepresent invention. At the very least, and not as an attempt to limit theapplication of the doctrine of equivalents to the scope of the claims,each numerical parameter should at least be construed in light of thenumber of reported significant digits and by applying ordinary roundingtechniques. Notwithstanding that the numerical ranges and parameterssetting forth the broad scope of the invention are approximations, thenumerical values set forth in the specific examples are reported asprecisely as possible. Any numerical value, however, inherently containscertain errors necessarily resulting from the standard deviation foundin their respective testing measurements.

The terms “a,” “an,” “the” and similar referents used in the context ofdescribing the invention (especially in the context of the followingclaims) are to be construed to cover both the singular and the plural,unless otherwise indicated herein or clearly contradicted by context.Recitation of ranges of values herein is merely intended to serve as ashorthand method of referring individually to each separate valuefalling within the range. Unless otherwise indicated herein, eachindividual value is incorporated into the specification as if it wereindividually recited herein. All methods described herein can beperformed in any suitable order unless otherwise indicated herein orotherwise clearly contradicted by context. The use of any and allexamples, or exemplary language (e.g., “such as”) provided herein isintended merely to better illuminate the invention and does not pose alimitation on the scope of the invention otherwise claimed. No languagein the specification should be construed as indicating any non-claimedelement essential to the practice of the invention.

Groupings of alternative elements or embodiments of the inventiondisclosed herein are not to be construed as limitations. Each groupmember may be referred to and claimed individually or in any combinationwith other members of the group or other elements found herein. It isanticipated that one or more members of a group may be included in, ordeleted from, a group for reasons of convenience and/or patentability.When any such inclusion or deletion occurs, the specification is deemedto contain the group as modified thus fulfilling the written descriptionof all Markush groups used in the appended claims.

Certain embodiments of this invention are described herein, includingthe best mode known to the inventors for carrying out the invention. Ofcourse, variations on these described embodiments will become apparentto those of ordinary skill in the art upon reading the foregoingdescription. The inventor expects skilled artisans to employ suchvariations as appropriate, and the inventors intend for the invention tobe practiced otherwise than specifically described herein. Accordingly,this invention includes all modifications and equivalents of the subjectmatter recited in the claims appended hereto as permitted by applicablelaw. Moreover, any combination of the above-described elements in allpossible variations thereof is encompassed by the invention unlessotherwise indicated herein or otherwise clearly contradicted by context.

In closing, it is to be understood that the embodiments of the inventiondisclosed herein are illustrative of the principles of the presentinvention. Other modifications that may be employed are within the scopeof the invention. Thus, by way of example, but not of limitation,alternative configurations of the present invention may be utilized inaccordance with the teachings herein. Accordingly, the present inventionis not limited to that precisely as shown and described.

1. A method of delivering a composition comprising: injecting through adelivery device into a location with physiological pH environment aliquid embolic composition comprising a biocompatible polymer includinga first monomer selected from a group consisting of aminopropylmethacrylamide, aminoethyl methacrylamide, aminoethyl methacylate,aminopropyl methacylate, N-(3-methylphridine)acrylamide,N-(2-(4-aminophenyl)ethylacrylamide, N-(4-aminobenzyl)acrylamide,N-(2-4-imidazolyl)ethyl)acrylamide, and combinations thereof, a secondmonomer, a non-physiological pH solution and a visualization agent, andwherein the biocompatible polymer precipitates when it reaches thephysiological pH.
 2. The method of claim 1, wherein the second monomercomprises an acrylate, acrylamide, a derivative thereof, or acombination thereof.
 3. The method of claim 1, wherein the visualizationagent is a particulate.
 4. The method of claim 1, wherein thevisualization agent is an iodinated compound, barium sulfate tantalum,superparamagnetic iron oxide, gadolinium molecules, or a combinationthereof.
 5. The method of claim 1, wherein the visualization agent has aconcentration of about 5% to about 65%.
 6. The method of claim 1,wherein the biocompatible polymer includes a third monomer.
 7. Themethod of claim 1, wherein the biocompatible polymer is a reactionproduct of three different monomers.
 8. The method of claim 1, whereinthe non-physiological pH solution is aqueous.
 9. The method of claim 1,wherein the non-physiological pH solution has a pH of less than about 5.10. The method of claim 1, wherein the non-physiological pH solution hasa pH of greater than about
 8. 11. The method of claim 1, wherein thebiocompatible polymer has a concentration of about 1% w/w to about 35%w/w.